G-protein coupled receptor 124 (GPR124), also known as Tumor Endothelial Marker 5 (TEM5), is an orphan receptor in the adhesion family of GPCRs. Previous global or endothelial-specific disruption of Gpr124 in mice led to defective CNS angiogenesis and blood brain barriergenesis. Similar developmental defects were observed following dual deletion of Wnt7a/Wnt7b or deletion of beta-catenin in endothelial cells, suggesting a possible relationship between GPR124 and canonical WNT signaling. Previously, we showed using in vitro reporter assays, mutation analysis and genetic interaction studies in vivo, that GPR124 functions as a potent WNT7A/WNT7B specific co-stimulator of beta-catenin signaling in brain endothelium. The remarkable specificity of this receptor for WNT7 was highlighted by the fact that GPR124 was unable to potentiate the activity of the other 17 WNT family members. Unlike previously described broad spectrum co-activators of WNT signaling, such as LRP5 and LRP6, our results provide a new paradigm that helps explain how precise WNT signaling specificity in vivo is governed, despite widespread overlapping expression of the 19 WNT ligands and 10 frizzled receptors in vivo, and the ability of most WNTs to signal though multiple frizzled receptors in vitro. A better understanding of how GPR124 potentiates WNT7 induced canonical beta-catenin signaling has important implications for understanding and manipulating CNS-specific angiogenesis, blood brain barriergenesis and potentially tumor angiogenesis. Our current work is aimed at identifying new binding partners that may help explain how Gpr124 is able to potentiate Wnt7 beta-catenin signaling.